The invention relates to compositions and methods for the treatment of proliferative disorders, including but not limited to cancer.
New cell antiproliferative agents, and anticancer therapeutics in particular, are needed which are useful in inhibiting proliferation of and/or killing cancer cells. In particular, such agents are needed which are selective in the killing of proliferating cells such as tumor cells, but not normal cells. Antineoplasitc agents are needed which are effective against a broad range of tumor types.
It is an object of the invention to provide compounds, compositions and therapeutic methods. The biologically active compounds are in the form of certain substituted (Z)-styrylbenzyl sulfones, and pharmaceutically acceptable salts thereof.
It is an object of the invention to provide compounds, compositions and methods for the treatment of cancer and other cell proliferative diseases.
It is an object of the invention to provide compounds which are selective in killing tumor cells but not normal cells.
It is an object of the invention to provide compounds, compositions and methods for inducing neoplastic cells to selectively undergo apoptosis.
In one aspect, the invention is directed to novel compounds of formula I: 
wherein:
R1 and R2 are independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1-C6)alkylamino(C2-C6 alkoxy) and trifluoromethyl; and
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1-C6)alkylamino(C2-C6 alkoxy) and trifluoromethyl; or
a pharmaceutically acceptable salt thereof.
In some embodiments, the benzyl nucleus (i.e., the ring system containing R3 and R4) is at least monosubstituted, that is, at least one of R3 and R4 is other than hydrogen.
In some embodiments, R1 and R2 are independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy and acetoxy, while R3 and R4 are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro and amino.
If the benzyl nucleus is substituted, the substituents in one embodiment are located at the 4- and/or 2-positions, that is, the compounds have the formula II: 
wherein R1, R2, R3 and R4 are defined as above, wherein at least one or both of R3 and R4 are other than hydrogen. In some embodiments, R4 is other than hydrogen, particularly halogen. In other embodiments, both R3 and R4 are other than hydrogen. According to certain embodiments, one or both of R3 and R4 are halogen, or all of R1, R2, R3 and R4 are halogen.
While any pattern of substitution for R1 and R2 is possible, i.e. 2/4, 2/3, or 3/4, 2/4 substitution is particularly preferred.
According to another embodiment of the invention, (Z)-styryl benzylsulfides are provided which are useful as intermediates in the preparation of (Z)-styryl benzylsulfones. The (Z)-styryl benzylsulfides have the formula: 
wherein R1, R2, R3 and R4 are defined as above with respect to formula I.
Selected embodiments of (Z)-styryl benzylsulfide compounds correspond directly to the above-described selected embodiments of (Z)-styryl benzylsulfide compounds, the only difference being the presence of the sulfide group as the precursor of the sulfone group; the latter results from oxidation of the former. For example, the sulfide analogs of the sulfones according to formula III have the formula IV: 
wherein R1, R2, R3 and R4 are defined as above with respect to formula III.
According to another embodiment of the invention, pharmaceutical compositions are provided comprising a pharmaceutically acceptable carrier and at least one compound according to formula I, or pharmaceutically acceptable salt thereof.
According to another embodiment of the invention, a method of treating an individual for a cell proliferative disorder comprises administering to said individual an effective amount of at least one compound according to formula I, or pharmaceutically acceptable salt thereof.
According to another embodiment of the invention, a method of inducing apoptosis of tumor cells in an individual afflicted with cancer is provided, comprising administering to said individual an effective amount of at least one compound according to formula I, or pharmaceutically acceptable salt thereof.
The term xe2x80x9calkylxe2x80x9d, by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated (i.e. C1-C6 means one to six carbons) and includes straight or branched chain groups. Most preferred is C1-C3 alkyl, particularly ethyl and methyl.
The term xe2x80x9calkoxyxe2x80x9d employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higher homologs and isomers. Preferred are C1-C3 alkoxy, particularly ethoxy and methoxy.
The term xe2x80x9c(C2-C6)acylaminoxe2x80x9d means a radical containing a two to six carbon straight or branched chain acyl group attached to a nitrogen atom via the acyl carbonyl carbon. Examples include xe2x80x94NHC(O)CH2CH2CH3 and xe2x80x94NHC(O)CH2CH2CH2CH2CH3.
The term xe2x80x9ccarboxy(C1-C3)alkoxyxe2x80x9d means a radical in which the carboxy group xe2x80x94COOH is attached to a carbon of a straight or branched chain alkoxy group containing one to three carbon atoms. The radical thus contains up to four carbon atoms. Examples include HOC(O)CH2CH2CH2Oxe2x80x94 and HOC(O)CH2CH2Oxe2x80x94.
The term xe2x80x9cdi(C1-C6)alkylamino(C2-C6)alkoxyxe2x80x9d means (alkyl)2N(CH2)nOxe2x80x94 wherein the two alkyl chains connected to the nitrogen atom independently contain from one to six carbon atoms, preferably from one to three carbon atoms, and n is an integer from 2 to 6. Preferably, n is 2 or 3. Most preferably, n is 2, and the alkyl groups are methyl, that is, the group is the dimethylaminoethoxy group, (CH3)2NCH2CH2Oxe2x80x94.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
The term xe2x80x9chydroxyalkylxe2x80x9d means an alkyl radical wherein one or more of the carbon atoms is substituted with hydroxy. Examples include xe2x80x94CH2CH(OH)CH3 and xe2x80x94CH2CH2OH.
The term xe2x80x9cphosphonatoxe2x80x9d means the group xe2x80x94PO(OH)2.
The term xe2x80x9csulfamylxe2x80x9d means the group xe2x80x94SO2NH2.
By xe2x80x9csubstitutedxe2x80x9d means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
By xe2x80x9csubjectxe2x80x9d is meant an animal or a human being.